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Impairment of ischemia-induced vascular functions by PS1 FAD mutants

PS1 FAD 突变体对缺血诱导的血管功能的损害

基本信息

批准号：
10328960
负责人：
Anastasios Georgakopoulos
金额：
$ 60.51万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-15 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10328960
关键词：
Adult Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient Angiogenic Factor Angiogenic Peptides Angiogenic Proteins Area Atrophic Attenuated Blood Blood Vessels Blood capillaries Blood flow Brain Brain Ischemia C-terminal Cerebrovascular Circulation Cerebrovascular Disorders Cerebrovascular system Chronic Cognitive Complex Data Defect Development ENG gene Endoglin Endothelial Cells Endothelium EphB4 Receptor Ephrin B Receptor Functional disorder Generations Growth Human Impairment Injury Intervention Ischemia Lesion Ligands Link Mediating Metabolic Molecular Mus Nerve Degeneration Neuronal Dysfunction Neurons Pathogenesis Pathologic Pathway interactions Peptides Pharmacologic Substance Play Production Proteins Proteolytic Processing Reporting Role Signal Transduction System Testing Tissues Toxic effect Vascular Diseases Vascular System angiogenesis base brain endothelial cell cadherin 5 cerebral microvasculature density familial Alzheimer disease gamma secretase genome-wide human disease in vivo ischemic lesion mouse model mutant neovascularization neuroimaging neuron loss neuronal survival neuropathology neurovascular novel protein complex protein expression raf-1 Protein receptor repaired response restoration tissue repair vascular abnormality

项目摘要

Cerebral microvasculature abnormalities, such as degeneration of the capillary endothelium, are implicated in the genesis of Alzheimer's disease (AD) neuropathology. In addition, ischemic lesions that cause neuronal damage are often found in AD brains. The brain responds to ischemia by stimulating tissue neovascularization via sprouting angiogenesis; impairment of this function renders the brain vulnerable to the insult. It has been hypothesized that decreased angiogenesis in AD leads to insufficient blood flow and neuronal dysfunction in affected areas. The EphB4/ephrinB2 (efnB2) ligand-receptor system is known to regulate brain angiogenesis in response to ischemia. We present evidence that Presnilin1 (PS1), an important factor in familial AD (FAD), regulates angiogenic functions of EphB4/efnB2 such as stimulation of VE-cadherin angiogenic complexes in brain endothelial cells (ECs). We also found that this function is impaired by PS1 FAD mutants. In addition, we found that ischemia stimulates formation of the same angiogenic complexes in the brain and that this function is attenuated by PS1 FAD mutants together with ischemia-induced neovascularization and cerebral blood flow while neuronal death is increased. We also found that PS1 FAD mutants decrease the γ-secretase processing of efnB2 and production of the angiogenic peptide efnB2/CTF2 thus impairing the response of brain ECs to angiogenic factors. Together, our data support the hypothesis that PS1 FAD mutants inhibit ischemia-induced angiogenic functions of ECs by decreasing the γ-secretase processing of efnB2 and impairing the EphB4/efnB2 signaling, thus decreasing neovascularization in the adult brain and leading to increased vulnerability to this toxic insult and neuronal death. In this application we examine the roles of PS1 FAD mutants and γ-secretase on ischemia-induced angiogenic complexes, blood flow, angiogenesis and neuronal death. In addition, we propose to test a small peptide, which derives from the proteolytic processing of efnB2 by γ-secretase and which we found to rescue angiogenic functions of PS1 FAD ECs, for its pro-angiogenic and neuroprotective functions in brains expressing FAD mutants. In addition we aim to search for novel ischemia-induced angiogenic pathways that are impaired by PS1 FAD mutants and examine whether VE-cadherin angiogenic complexes and angiogenic protein expression are impaired in brains of human PS1 FAD and AD patients.

脑微血管异常，如毛细血管内皮的退化，涉及